The present invention relates to methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes can be improved.
A group of compounds that stimulate insulin secretion and stimulate de novo synthesis of insulin are the cAMP phosphodiesterase type 3 inhibitors. It is believed that cAMP phosphodiesterase type 3 inhibitors act to increase insulin secretion by increasing intracellular levels of cAMP in pancreatic xcex2-cells in the islet of Langerhans. In contrast, sulfonylureas act on the K+ ATP channels of pancreatic xcex2-cells in the islet of Langerhans. Moreover, cAMP phosphodiesterase type 3 is known to exist in two forms: type A and type B. Type A cAMP phosphodiesterase 3 is associated with cardiac tissue and with platelets, and type B is associated with liver and adipose tissue, and xcex2-cells in the pancreas.
In addition to sulfonylureas, which stimulate insulin secretion by acting on the K+ ATP channels, a group of non-sulfonylureas are known to stimulate insulin secretion by acting on K+ ATP channels. Examples of such non-sulfonylurea insulin secretagogues include nateglinide and repaglinide.
The present invention provides an improved method of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance using a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
In addition, the present invention relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance.
The present invention provides methods of treating non-insulin dependent diabetes mellitus, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
Also provided are methods of treating insulin resistance, the methods comprising the step of administering to a patient having or at risk of having insulin resistance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
Also provided are methods of treating Syndrome X, the methods comprising the step of administering to a patient having or at risk of having Syndrome X a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
Also provided are methods of treating diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, or cataracts, the methods comprising the step of administering to a patient having or at risk of having diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, or cataracts a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
Also provided are methods of treating hyperglycemia, the methods comprising the step of administering to a patient having or at risk of having hyperglycemia a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
Also provided are methods of treating impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor.
Also provided are pharmaceutical compositions comprising a sulfonylurea and/or non-sulfonylurea K+ ATP channel blocker, and a cAMP phosphodiesterase type 3 inhibitor.
Also provided are pharmaceutical compositions comprising a sulfonylurea and a cAMP phosphodiesterase type 3 inhibitor.
Also provided are pharmaceutical compositions comprising a non-sulfonylurea K+ ATP channel blocker and a cAMP phosphodiesterase type 3 inhibitor.
Also provided are pharmaceutical compositions comprising a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, and a cAMP phosphodiesterase type 3 inhibitor.
Also provided are kits for the treatment of non-insulin dependent diabetes mellitus, the kits comprising:
a) a first pharmaceutical composition comprising: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor;
b) a second pharmaceutical composition comprising a second compound useful for the treatment of non-insulin dependent diabetes mellitus; and
c) a container for the first and second compositions.
In a preferred embodiment of the kits, the second compound is selected from:
insulin and insulin analogs;
GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH2;
biguanides;
glycogen phosphorylase inhibitors;
aldose reductase inhibitors;
xcex12-antagonists;
imidazolines;
glitazones (thiazolidinediones);
PPAR-gamma agonists;
fatty acid oxidation inhibitors;
xcex1-glucosidase inhibitors;
xcex2-agonists;
lipid-lowering agents;
antiobesity agents;
vanadate, vanadium complexes and peroxovanadium complexes;
amylin antagonists;
glucagon antagonists;
gluconeogenesis inhibitors;
somatostatin agonists and antagonists; or
antilipolytic agents.
In a more preferred embodiment of the kits, the second compound is selected from LysPro insulin, GLP-1 (7-37) (insulinotropin), GLP-1 (7-36)-NH2, metformin, phenformin, buformin, midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone, clomoxir, etomoxir, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, benfluorex, fenfluramine, Naglivan(copyright), acipimox, WAG 994, Symlin(trademark), or AC2993.
In another preferred embodiment of the kits, the second compound is selected from insulin, biguanides, or thiazolidinediones.
Also provided are kits for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the kits comprising:
a) a first pharmaceutical composition comprising: 1) a sulfonylurea, a non-sulfonylurea K+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor;
b) a second pharmaceutical composition comprising a second compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance; and
c) a container for the first and second compositions.
Also provided are kits for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the kits comprising:
a) a first pharmaceutical composition comprising a sulfonylurea or a non-sulfonylurea K+ ATP channel blocker;
b) a second pharmaceutical composition comprising a cAMP phosphodiesterase type 3 inhibitor; and
c) a container for the first and second compositions.
In a preferred embodiment of the methods, kits, and pharmaceutical compositions, the sulfonylurea is glyburide and the cAMP phosphodiesterase type 3 inhibitor is milrinone.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the cAMP phosphodiesterase type 3 inhibitor is a selective cAMP phosphodiesterase type 3B inhibitor.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the sulfonylurea is glyburide, chlorpropamide, glibenclamide, glipizide, gliclazide, glimepiride, tolbutamide, acetohexamide, or tolazamide.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the sulfonylurea is glipizide or glyburide.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the sulfonylurea is glyburide.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the cAMP phosphodiesterase type 3 inhibitor is milrinone, amrinone, enoximone, indolidan, cilostamide, lixazinone, imazodan, cilostazol, bemorandan, siguazodan, adibendan, pimobendan, saterinone, sulmazol, or vesnarinone.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the cAMP phosphodiesterase type 3 inhibitor is milrinone.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the cAMP phosphodiesterase type 3 inhibitor is milrinone and the sulfonylurea is glyburide.
In another preferred embodiment of the methods, kits, and pharmaceutical compositions, the non-sulfonylurea K+ ATP channel blocker is repaglinide or nateglinide.